Trial Information

Phase I Study of the Aurora Kinase A Inhibitor MLN8237 in Combination With the Histone Deacetylase Inhibitor Vorinostat in Lymphoid Malignancies

PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) of alisertib (MLN8237) when given in
combination with vorinostat and to select a dose and schedule for further testing
(recommended Phase 2 dose: RP2D) in patients with lymphoid malignancies.

II. To describe the toxicities of MLN8237 when given in combination with vorinostat on a
21-day schedule.

III. To determine any clinical responses with MLN8237 in combination with vorinostat.

IV. To compare the plasma pharmacokinetics of MLN8237 when given alone and in combination
with vorinostat.

V. To perform immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH)
analysis to determine aurora kinase A (AURKA) expression in archival formalin-fixed
paraffin-embedded sections from the most recent available tumor specimens of patients.

VI. To perform correlative studies for apoptosis and proliferation on bone marrow and lymph
node specimens, where available, obtained from patients in the expanded cohort at RP2D.

OUTLINE: This is a dose-escalation study of alisertib.

Patients receive alisertib orally (PO) twice daily (BID) on days 1-7 and vorinostat PO BID
on days 1-14. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 30 days.

Inclusion Criteria:

- Patients must have a histologically or cytologically confirmed lymphoid malignancy
(like Hodgkin lymphoma or one of the mature B- or T-cell non-Hodgkin lymphomas as
classified by World Health Organization [WHO]) for which standard curative or
palliative measures do not exist or are no longer effective

- Patients must have measurable disease in two dimensions and >= 2 cm is acceptable (or
1.5 cm if 0.5 slices are used, as in spiral computed tomography [CT] scans); lesions
that are considered intrinsically non-measurable include the following:

- Bone lesions

- Leptomeningeal disease

- Ascites

- Pleural/pericardial effusion

- Inflammatory breast disease

- Lymphangitis cutis/pulmonis

- Abdominal masses that are not confirmed and followed by imaging techniques

- Cystic lesions

- Lesions that are situated in a previously irradiated area

- Patients must have had at least 1 prior systemic chemotherapy (not just steroids or
local radiation)

- Patients with known brain metastases should be excluded from this clinical trial

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and 4 months after completion of MLN8237
administration

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to MLN8237 including, but not limited to, established allergic
reaction to benzodiazepines

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with MLN8237

- No known history of uncontrolled sleep apnea syndrome or other conditions that could
result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary
disease

- No requirement for supplemental oxygen

- No conditions that could result in excessive toxicity associated with the
benzodiazepine-like effects of MLN8237

- No inability to swallow oral medication or to maintain a fast as required for 2 hours
before and 1 hour after MLN8237 administration or any condition that would modify
small bowel absorption of oral medications, including malabsorption, or resection of
pancreas or upper bowel

- No patients with New York Heart Association (NYHA) Class II-IV heart failure

- See Disease Characteristics

- Last chemotherapy or radiation must be at least 4 weeks prior to enrollment on this
study

- Patients who decline other potentially curative therapy may be eligible

- Prior radiation therapy must not have been to more than 25% of the bone marrow

- Whole pelvic radiation is considered to be over 25%

- Prior allogeneic stem cell transplant patients will be allowed to enroll if they are
past day +100 of transplant, have no active graft-versus-host-disease, are not on any
immunosuppressants, and have been off immunosuppressants for at least 4 weeks

- Prior autologous stem cell transplant patients will be allowed to enter this study if
they are past their day +100 of transplant

- No patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- No patients who are receiving any other investigational agents

- No treatment with valproic acid within 14 days prior to initiation of study and
during the study

- No prior use of valproic acid or any other histone deacetylase (HDAC) inhibitor
for lymphoma treatment

- No treatment with clinically significant enzyme inducers, such as the enzyme-inducing
antiepileptic drugs phenytoin, carbamazepine, oxcarbazepine, primidone or
phenobarbital; rifampin, rifabutin, rifapentine; or St. John wort within 14 days
prior to the first dose of MLN8237 and during the study

Type of Study:

Interventional

Study Design:

Outcome Measure:

MTD of alisertib defined as the highest dose tested in which less than 33% of patients experienced dose-limiting toxicity (DLT) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0

Outcome Description:

The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by NCI CTCAE version 4.0) and nadir or maximum values for the laboratory measures, time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course.

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